Medical device with a porous surface for delivery of a therapeutic agent

ABSTRACT

The present invention is generally directed to implantable medical devices for delivering therapeutic agents to the body tissue of a patient and methods for making such medical devices. In particular, the present invention is directed to implantable medical devices, such as intravascular stents, having a surface that includes a plurality of cavities and a plurality of pores and a composition disposed in the pores and/or cavities, as well as, implantable medical devices, such as intravascular stents, having a surface that has a coating composition disposed on the surface, wherein the coating composition includes a plurality of cavities and a plurality of pores and another coating composition disposed in the pores and/or cavities.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.60/904,674, filed Mar. 1, 2007.

FIELD OF THE INVENTION

The present invention is generally directed to implantable medicaldevices for delivering therapeutic agents to the body tissue of apatient and methods for making such medical devices. In particular, thepresent invention is directed to implantable medical devices, such asintravascular stents, having a surface that includes a plurality ofcavities and a plurality of pores and a composition disposed in thepores and/or cavities, as well as, implantable medical devices, such asintravascular stents, having a surface that has a coating compositiondisposed on the surface, wherein the coating composition includes aplurality of cavities and a plurality of pores and another coatingcomposition disposed in the pores and/or cavities.

BACKGROUND

Medical devices have been used to deliver therapeutic agents locally tothe body tissue of a patient. For example, stents having a coatingcontaining a therapeutic agent, such as an anti-restenosis agent, can beeffective in treating or preventing restenosis. Currently, such medicaldevice coatings include a therapeutic agent alone or a combination of atherapeutic agent and a polymer. Both of these types of coatings sufferfrom certain limitations.

Coatings containing a therapeutic agent without a polymer are generallyimpractical since such coatings offer little or no control over the rateof release of the therapeutic agent. Therefore, many medical devicecoatings include a therapeutic agent and a polymer.

Though the use of polymers can provide control over the rate of releaseof the therapeutic agent, the use of such polymers in coatings may posecertain other limitations. For example, some polymer coatingcompositions do not actually adhere to the surface of the medicaldevice. In order to ensure that the coating compositions remain on thesurface, the area of the medical device that is coated, such as a stentstrut, is encapsulated with the coating composition. However, since thepolymer does not adhere to the medical device, the coating compositionis susceptible to deformation and damage during loading, deployment andimplantation of the medical device. Any damage to the polymer coatingmay alter the therapeutic agent release profile and can lead to anundesirable increase or decrease in the therapeutic agent release rate.Also, polymer in the coatings may react with the blood and cause latestage thrombosis.

For instance, balloon expandable stents must be put in an unexpanded or“crimped” state before being delivered to a body lumen. During thecrimping process coated stent struts are placed in contact with eachother and can possibly adhere to each other. When the stent is expandedor uncrimped, the coating on the struts that have adhered to each othercan be damaged, torn-off or otherwise removed. Moreover, if the polymercoating is applied to the inner surface of the stent, it may stick oradhere to the balloon used to expand the stent when the balloon contactsthe inner surface of the stent during expansion. Such adherence to theballoon may prevent a successful deployment of the medical device.

Similar to balloon-expandable stents, polymer coatings on self-expandingstents can also interfere with the delivery of the stent. Self-expandingstents are usually delivered using a pull-back sheath system. When thesystem is activated to deliver the stent, the sheath is pulled back,exposing the stent and allowing the stent to expand itself. As thesheath is pulled back it slides over the outer surface of the stent.Polymer coatings located on the outer or abluminal surface of the stentcan adhere to the sheath as it is being pulled back and disrupt thedelivery of the stent.

An alternative to coating or encapsulating the surface of a medicaldevice is to create pores within the surface of the medical device anddispose a therapeutic agent within the pores. Though the use of a poroussurface overcomes certain limitations of using a polymer coating, due tothe small size of the pores the therapeutic agent may only penetrate toa certain depth of the porous coating. Such insufficient penetration canresult in a limited amount of the therapeutic agent that can be loadedonto the medical device, as well as, an unwanted rate of release wherethe therapeutic agent is released over a short period of time. Also dueto the limited surface area of the surface of the medical device, alimited number of pores and therefore, a limited amount of a therapeuticagent can be loaded onto the surface of the medical device.

Accordingly, there is a need for medical devices and coatings formedical devices that have little or no polymer and that can release aneffective amount of a therapeutic agent in a controlled release mannerwhile avoiding the disadvantages of current coatings for medicaldevices. Also, there is a need for coatings that can release aneffective amount of a therapeutic agent in a controlled release mannerthat can be selectively applied to the surfaces of a medical device,such as the surfaces that contact the body tissue of a patient.Additionally, there is a need for methods of making such medical devicesand coatings for medical devices.

SUMMARY

As used herein, and unless otherwise indicated, the terms “controlledrelease,” “sustained release”, “modulated release” and “modifiedrelease” can be used interchangeably and are used to describe therelease profile of a therapeutic agent that is not an immediate releaseprofile.

These and other objectives are accomplished by the present invention.The present invention provides a coating for a medical device, such asan intravascular stent, that is capable of releasing an effective amountof a therapeutic agent in a controlled release manner, without thelimitations associated with current coatings, including polymercoatings. The coatings of the present invention can be applied to selectsurfaces of a medical device such as the medical device surfaces thatcontact the surface of a body lumen of a patient. Such selectiveapplication of the coatings of the present invention can increase theaccuracy and economical use of a therapeutic agent.

In certain embodiments of the present invention, the coatings of thepresent invention include a first coating composition having a metal, ametal oxide, ceramic oxide, or inert carbon and a plurality of cavitiesand a plurality of pores within the first coating composition. At leastsome of the pores are formed on the surface of the cavities. Thecoatings also include a second coating composition having a therapeuticagent disposed in at least one of the pores.

For example, the present invention includes an implantable stentcomprising a stent sidewall structure, such as a tubular stent sidewallstructure, having a surface and a coating that includes a first coatingcomposition disposed on at least a portion of the surface of the stentsidewall structure. The first coating composition has an exposed surfaceand includes a metal, a metal oxide, ceramic oxide, or inert carbonhaving a plurality of cavities therein. Some of the cavities are influid communication with the exposed surface and at least one of thecavities is defined by a cavity surface having a plurality of porestherein. The coating also includes a second coating compositioncomprising a first therapeutic agent, wherein the second coatingcomposition is disposed within at least one of the pores.

In the above example, at least one of the pores of the first coatingcomposition can be in fluid communication with the cavity surface.Additionally, the pores can be distributed throughout the first coatingcomposition. In certain embodiments the pores can be homogenouslydistributed throughout the first coating composition.

Also, in the above described example, the second coating composition canalso be disposed within at least one of the cavities. In certainembodiments, the second coating composition further includes a polymer.

The coatings of the present invention can further include a thirdcoating composition having a second therapeutic agent, a polymer or botha therapeutic agent and a polymer. The third coating composition canalso be disposed in at least one of the cavities.

Suitable stents for the embodiments described herein can have a sidewallstructure having an abluminal surface having a plurality of struts andopenings in the sidewall structure. In certain embodiments, the surfaceof the stent sidewall is the abluminal surface. The first composition,second composition or third coating composition can conform to thesurface of the stent so that the openings in the stent sidewallstructure are preserved. Examples of such suitable stents include, butare not limited to, intravascular stents such as intravascularballoon-expandable stents and intravascular self-expanding stents.

The first coating composition can be free of any polymer. Additionally,the first coating composition can be radiopaque. For the first coatingcomposition, suitable metal oxides or ceramic oxides include but are notlimited to, iridium oxide, titanium oxide, titanium dioxide, iron oxide,hydroxyapatite, calcium phosphates, alumina, zirconia, zirconium, silicabased glasses, or a combination thereof. For the first coatingcomposition, suitable metals include but are not limited to, goldtantalum, platinum, titanium, Nitinol or a combination thereof.

The first coating composition can have a thickness of about 1 micron toabout 30 microns. The diameter or width of the pores in the firstcoating composition can be less than or equal to about one micron. Thesize of the cavities in the first coating composition can be greaterthan or equal to about one micron.

In other embodiments of the present invention, the present inventionincludes, an implantable stent having a stent sidewall structure, suchas a tubular stent sidewall structure having a surface, wherein thestent sidewall structure includes a metal, a metal oxide, ceramic oxideor inert carbon having a plurality of cavities therein. At least some ofthe cavities can be in fluid communication with the surface and at leastone cavity is defined by a cavity surface having a plurality of porestherein. The stent also includes a first composition that includes afirst therapeutic agent, wherein the first composition is disposedwithin at least some of the pores.

In the above embodiments, at least one of the pores can be in fluidcommunication with the cavity surface. The pores can be distributedthroughout the stent sidewall structure. For example, the pores can behomogenously distributed throughout the stent sidewall structure.

The diameter or width of the pores in the cavity surface can be lessthan or equal to about one micron. The size of the cavities in the stentsidewall structure can be greater than or equal to about one micron. Thestent sidewall structure can be radiopaque. Suitable metal oxides orceramic oxides for the stent sidewall structure include, but are notlimited, iridium oxide, titanium oxide, titanium dioxide, iron oxide,hydroxyapatite, calcium phosphates, alumina, zirconia, zirconium, silicabased glasses, or a combination thereof. For the first coatingcomposition, suitable metals include but are not limited to

Suitable metals for the stent sidewall structure include but are notlimited to, gold, tantalum, platinum, titanium, Nitinol or a combinationthereof.

The first composition can also be disposed in at least one of thecavities. The first coating composition can further include a polymer.Alternatively, the stents of the present invention can further include asecond composition having a second therapeutic agent, a polymer or botha therapeutic agent and a polymer, wherein the second composition isdisposed in at least some of the cavities. Also, the second compositioncan also be disposed within at least one of the pores.

Polymers in any of the above discussed embodiments of the coatings ofthe present invention can include biostable and bioabsorbable polymers.Suitable polymers include, but are not limited to,styrene-isobutylene-styrene, polylactic-co-glycolic acid (PLGA),polybutyl methacrylate (PBMA), polyvinylidene fluoride (PVDF), or acombination thereof.

Suitable stents for the embodiments described herein can have a sidewallstructure having an abluminal surface having a plurality of struts andopenings in the sidewall structure. In certain embodiments, the firstcomposition and/or second composition can conform to the surface of thestent so that the openings in the stent sidewall structure arepreserved. Examples of such suitable stents include, but are not limitedto intravascular stents such as intravascular balloon-expandable stentsand intravascular self-expanding stents.

Suitable therapeutic agents that can be included in the coatings of thepresent invention include, but are not limited, to anti-thrombogenicagents, anti-angiogenesis agents, anti-proliferative agents, antibiotic,anti-restenosis agents, growth factors, immunosuppressants orradiochemicals. In some preferred embodiments the therapeutic agent isan anti-restenosis agent. More specifically, suitable therapeutic agentsinclude, but are not limited to, paclitaxel, sirolimus, tacrolimus,pimecrolimus, zotarolimus or everolimus. When the embodiments of thepresent invention include a first and second therapeutic agent the firsttherapeutic agent and second therapeutic agent can be the same ordifferent.

The present invention is also directed to methods of coating a medicaldevice having a surface. For example the present invention includes amethod of coating an implantable stent having a surface that includesthe steps of (a) disposing a first coating composition on the surface,wherein the first coating composition includes a metal, a metal oxide,ceramic oxide or inert carbon; (b) creating a plurality of cavities inthe first coating composition, wherein the cavities have a cavitysurface; (c) creating a plurality of pores within the cavity surface;and (d) disposing a second coating composition within at least one ofthe pores, wherein the second coating composition comprises a firsttherapeutic agent.

The methods of the present invention also include a method of coating animplantable stent having a surface that includes the steps of (a)disposing a first coating composition on the surface, wherein the firstcoating composition includes a metal, a metal oxide, ceramic oxide orinert carbon, and wherein the first coating composition comprises aplurality of pores therein; (b) creating a plurality of cavities in thefirst coating composition; and (c) disposing a second coatingcomposition within at least one of the pores, wherein the second coatingcomposition comprises a first therapeutic agent. The plurality of porescan be formed or created or they can be naturally occurring in themetal, metal oxide, ceramic oxide or inert carbon.

The above described methods can further include disposing the secondcoating composition within at least some of the cavities. The secondcoating composition can also include a polymer. In certain embodimentsthe above methods can further include disposing a third coatingcomposition within at least some of the cavities, wherein the thirdcoating composition comprises a second therapeutic agent, a polymer orboth a second therapeutic agent and a polymer. The cavities can beformed by laser ablation, drilling, chemical etching or a combinationthereof.

The methods of the present invention also include, for example, a methodof coating an implantable stent having a surface that includes a metal,a metal oxide, ceramic oxide or inert carbon having a plurality of porestherein, the method includes the steps of (a) creating a plurality ofcavities in the surface, wherein the cavities have a cavity surface andwherein at least some of the pores are in fluid communication with aportion of the cavity surface; and (b) disposing a first compositioncomprising a first therapeutic agent within at least some of the pores.The plurality of pores can be formed or created or they can be naturallyoccurring in the metal, metal oxide, ceramic oxide or inert carbon.

The methods of the present invention also include a method of coating animplantable stent having a surface that includes a metal, a metal oxide,ceramic oxide or inert carbon, the method includes the steps of: (a)creating a plurality of cavities in the metal, metal oxide, ceramicoxide or inert carbon, wherein the cavities have a cavity surface; (b)creating a plurality of pores in the metal, metal oxide, ceramic oxideor inert carbon and wherein at least some of the pores are in fluidcommunication with a portion of the cavity surface; and (c) disposing afirst composition having a first therapeutic agent within at least someof the pores.

The above described methods can further include disposing the firstcomposition within at least some of the cavities. The first compositioncan further include a polymer. Alternatively, the methods can furtherinclude disposing a second composition within at least some of thecavities, wherein the second composition includes a second therapeuticagent, a polymer or a second therapeutic agent and a polymer. Thecavities can be formed by laser ablation, drilling, chemical etching ora combination thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be explained with reference to the followingdrawings.

FIG. 1 shows an example of a medical device that is suitable for use inthe present invention.

FIG. 2 shows a cross-sectional view of an embodiment of a coatingcomposition having cavities and pores disposed on a portion of a stent.

FIG. 3 shows a cross-sectional view of another embodiment of a coatingcomposition having cavities and pores disposed on a portion of a stent.

FIG. 4 shows a cross-sectional view of an embodiment of a first coatingcomposition having cavities and pores disposed on a portion of a stent,wherein the pores and cavities contain a second coating composition.

FIG. 5 shows a cross-sectional view of another embodiment of a firstcoating composition having cavities and pores disposed on a portion of astent, wherein the pores and cavities contain a second coatingcomposition.

FIG. 6 shows a cross-sectional view of still another embodiment of afirst coating composition having cavities and pores disposed on aportion of a stent, wherein the pores and cavities contain a secondcoating composition.

FIG. 7 shows a cross-sectional view of still another embodiment of afirst coating composition having cavities and pores disposed on aportion of a stent, wherein the pores and cavities contain a secondcoating composition.

FIG. 8 shows a cross-sectional view of a portion of a stent strut havingcavities and pores therein.

DETAILED DESCRIPTION

In certain embodiments, the medical devices of the present inventionhave a surface that has a coating disposed thereon. The coating includesa first coating composition that includes a metal, a metal oxide,ceramic oxide or inert carbon having a plurality of cavities therein.Also, when the first coating composition is disposed on the surface, thefirst coating composition has an exposed surface that is in fluidcommunication with some of the cavities. At least one of the cavities isdefined by a cavity surface having a plurality of pores therein. Thecoatings further include a second coating composition having a firsttherapeutic agent disposed within at least one of the pores.

FIG. 1 shows an example of a medical device that is suitable for use inthe present invention. This figure shows an implantable intravascularstent 10. As shown in FIG. 1 intravascular stent 10 is unrolled, but isgenerally cylindrical in shape. Stent 10 includes a sidewall 20 whichcomprises a plurality of struts 30 and at least one opening 40 in thesidewall 20. Generally, the opening 40 is disposed between adjacentstruts 30. Also, the stent sidewall structure 20 may have a firstsidewall surface 22 and an opposing second sidewall surface 54, which isnot shown in FIG. 1 but can be seen in FIG. 2. The first sidewallsurface 22 can be an outer or abluminal sidewall surface, which faces abody lumen wall when the stent is implanted, or an inner or luminalsidewall surface, which faces away from the body lumen surface.Likewise, the second sidewall surface can be an abluminal sidewallsurface or a luminal sidewall surface.

When the coatings of the present invention are applied to a stent havingopenings in the stent sidewall structure, in certain embodiments, it ispreferable that the coatings conform to the surface of the stent so thatthe openings in the sidewall stent structure are preserved, e.g. theopenings are not entirely or partially occluded with coating material.

FIG. 2 shows a cross-sectional view of an embodiment of a coating of thepresent invention disposed on a stent strut. Stent strut 50 has asurface, such as an abluminal surface 52 and a luminal surface 54. Inthis embodiment, coating 60 is disposed on the abluminal surface 52 ofstent strut 50. Coating 60 comprises a first coating composition 70comprising a metal, a metal oxide, ceramic oxide or an inert carbon. Incertain embodiments, the first coating composition is free of anypolymer, or substantially free of any polymer, i.e. contains less than50% polymer by weight of the first coating composition. The firstcoating composition 70 has an exposed surface 72. An exposed surface isan outer surface that is capable of contacting body tissue when thedevice is inserted or implanted and is not covered by another material.The first coating composition 70 also includes a plurality of cavities74 therein, in which at least some of the cavities are in fluidcommunication with the exposed surface 72. When the cavities are influid communication with the exposed surface, materials or fluids placedin the cavity can come into contact with the exposed surface. Thecavities 74 have a cavity surface 76, i.e. a surface that defines thecavity. Additionally, the first coating composition includes a pluralityof pores 78, at least some of which are in fluid communication withcavity surface 76. When the pores are in fluid communication with thecavity surface, materials or fluids placed in the pores can come intocontact with the cavity surface. As shown in this embodiment, the poresare disposed on or near the cavity surface. Disposed within some of thepores 78 is a second coating composition comprising a therapeutic agent80. The cavities increase the surface area of the coating and allow thetherapeutic agent to penetrate deeper into the coating.

FIG. 3 shows a cross-sectional view of a coating of the presentinvention disposed on a surface of a stent strut. As shown in FIG. 3,stent strut 50 has an abluminal surface 52 and a luminal surface 54. Inthis embodiment, coating 60 is disposed on the abluminal surface 52 ofstent strut 50. Coating 60 comprises a first or surface coatingcomposition 70 comprising a metal, a metal oxide, ceramic oxide or aninert carbon, wherein the first coating composition 70 has an exposedsurface 72. The first coating composition 70 also has a plurality ofcavities 74 at least some of which are in fluid communication with theexposed surface 72. The cavities 74 have a cavity surface 76.Additionally, the first coating composition includes a plurality ofpores 78 positioned throughout the first coating composition, some ofwhich are in fluid communication with cavity surface 76. Disposed withinsome of the pores 78 is a second coating composition 79 comprising atherapeutic agent 80.

The location and number of pores can vary depending on the desiredamount of therapeutic agent that is to be loaded onto the coating aswell as the desired therapeutic agent release profile. Pores can be in adiscreet area such as on or near the cavity surface, as shown in FIG. 2or throughout the first coating composition, as shown in FIG. 3. Incertain embodiments, pores can be homogeneously, i.e. evenly,distributed throughout the first coating composition. In otherembodiments, the pores may be disposed in a pattern. Patterns can berandom or uniform.

FIG. 4 shows a cross-sectional view of a coating of the presentinvention disposed on a surface of a stent strut. The stent strut 50 hasan abluminal surface 52 and a luminal surface 54. In this embodiment,coating 60 is disposed on the abluminal surface 52 of stent strut 50.Coating 60 comprises a first coating composition 70 comprising a metal,a metal oxide, ceramic oxide or an inert carbon, wherein the firstcoating composition 70 has an exposed surface 72. The first coatingcomposition 70 also has a plurality of cavities 74 at least some ofwhich are in fluid communication with the exposed surface 72. Thecavities 74 have a cavity surface 76. Additionally, the first coatingcomposition includes a plurality of pores 78, some of which are in fluidcommunication with a cavity surface 76. As shown in this embodiment,disposed within some of the cavities 74 and pores 78 is a second coatingcomposition comprising a therapeutic agent 80. The benefit to disposingthe therapeutic agent in both the cavities and the pores is to allow fora therapeutic agent release profile that has a quick release and acontrolled release profile. The therapeutic agent in the cavities canrelease quickly into the body lumen, thus displaying a “burst effect.”After the therapeutic agent has released from the cavities thetherapeutic agent disposed in the pores can then release more slowlydisplaying a more controlled release profile. Additionally, once therelease of the therapeutic agent is complete, having the cavities incommunication with the exposed surface can aid in vascularization andcell coverage for long-term non-inflammation.

FIG. 5 shows a cross-sectional view of a coating of the presentinvention disposed on a surface of a stent strut. As shown in FIG. 5,stent strut 50 has an abluminal surface 52 and a luminal surface 54. Inthis embodiment, coating 60 is disposed on the abluminal surface 52 ofstent strut 50. Coating 60 comprises a first coating composition 70comprising a metal, a metal oxide, ceramic oxide or an inert carbon,wherein the first coating composition 70 has an exposed surface 72. Thefirst coating composition 70 also has a plurality of cavities 74 atleast some of which are in fluid communication with the exposed surface72. The cavities 74 have a cavity surface 76. Additionally, the firstcoating composition includes a plurality of pores 78, some of which arein fluid communication with a cavity surface 76. As shown in thisembodiment, disposed within some of the pores 78 is a second coatingcomposition 79 comprising a first therapeutic agent 80 and disposedwithin some of the cavities 76 is a third coating composition 81comprising a second therapeutic agent 82. In other embodiments, thethird coating composition can comprise at least one therapeutic agent, apolymer, or alternatively a therapeutic agent and a polymer. In FIG. 5,the third coating composition comprises a second therapeutic agent 82,wherein the first therapeutic agent and the second therapeutic agent aredifferent.

Though, in FIGS. 2 through FIG. 5, the coating is disposed on theabluminal surface, which is the portion of the surface of the stent thatfaces a lumen wall, the coatings of the present invention can be appliedto any surface of a medical device. In alternative embodiments, thecoating can be disposed on a portion of a surface of a medical devicethat does not contact a lumen wall. Such embodiments can be useful when,in addition to administering a therapeutic agent to a lumen wall, it isalso beneficial to introduce a therapeutic agent into the blood stream.For example, an intravascular stent having an abluminal and luminalsurface can have the coating of the present invention disposed on boththe abluminal and luminal surfaces. A coating on the abluminal surfacecan administer a therapeutic agent to a lumen wall and a coating on theluminal surface can introduce a therapeutic agent into the blood stream.

When a coating is disposed on both the abluminal and luminal surfaces ofa stent, the coating disposed on the abluminal surface can be the sameas or different from the coating disposed on the luminal surface of thestent. Also, the therapeutic agent disposed in the cavities of thecoating on the abluminal and luminal sides can be the same or different.

Though the coatings of the present invention can provide controlledrelease of a therapeutic agent without the need for a polymer matrix, asshown in the coatings in FIGS. 1-5, in certain embodiments a polymer maybe included in the coating compositions of the present invention. Insome embodiments, the second coating composition can include a polymer.For example, a bioabsorbable polymer can be used to slow the release ofthe therapeutic agent disposed in the pores. A bioabsorbable polymer iscapable of releasing the therapeutic agent as the polymer is beingabsorbed. A biostable polymer, which is not absorbed into the body, canalso be used. For example, a biostable polymer can also be used to slowthe release rate of the therapeutic agent by forcing the therapeuticagent to travel through the porous network to the coating surface.

In some embodiments, as shown in FIG. 6, the coatings of the presentinvention can further include a third coating composition, disposed inthe cavities, wherein the third coating composition includes a polymer.FIG. 6 shows a cross-sectional view of a coating of the presentinvention disposed on a surface of a stent strut. As shown in FIG. 6,stent strut 50 has an abluminal surface 52 and a luminal surface 54. Inthis embodiment, coating 60 is disposed on the abluminal surface 52 ofstent strut 50. Coating 60 includes a first coating composition 70having a metal, a metal oxide, ceramic oxide or inert carbon, whereinthe first coating composition 70 has an exposed surface 72. The firstcoating composition 70 also has a plurality of cavities 74, at leastsome of which are in fluid communication with the exposed surface 72.The cavities 74 have a cavity surface 76. Additionally, the firstcoating composition includes a plurality of pores 78, some of which arein fluid communication with a cavity surface 76. As shown in thisembodiment, disposed within some of the pores 78 is a second coatingcomposition comprising a first therapeutic agent 80 and disposed withinsome of the cavities 76 is a third coating composition that includes apolymer 84. In other embodiments, the third coating composition can alsoinclude a therapeutic agent, wherein the therapeutic agent can be thesame or a different therapeutic agent than that included in the firstcoating composition.

In some embodiments, as shown in FIG. 7, the coatings of the presentinvention can further include a third coating composition, disposed in aportion of the cavities, wherein the third coating composition includesa polymer. FIG. 7 shows a cross-sectional view of a coating of thepresent invention disposed on a surface of a stent strut. As shown inFIG. 7, stent strut 50 has an abluminal surface 52 and a luminal surface54. In this embodiment, coating 60 is disposed on the abluminal surface52 of stent strut 50. Coating 60 includes a first coating composition 70having a metal, a metal oxide, ceramic oxide or inert carbon, whereinthe first coating composition 70 has an exposed surface 72. The firstcoating composition 70 also has a plurality of cavities 74, at leastsome of which are in fluid communication with the exposed surface 72.The cavities 74 have a cavity surface 76. Additionally, the firstcoating composition includes a plurality of interconnected pores 78,some of which are in fluid communication with a cavity surface 76. Asshown in this embodiment, disposed within some of the pores 78 andwithin a portion of some of the cavities 74 is a second coatingcomposition that includes a first therapeutic agent 80. Also disposedwithin a portion of some of the cavities 76 is a third coatingcomposition that includes a polymer 84. The therapeutic agent 80disposed in a portion of at least some of the cavities 74 can serve as areservoir while the third coating composition that includes a polymer 84can serve as a cap, forcing the therapeutic agent 80 to travel throughthe porous network to the coating surface 72.

FIG. 8 shows a cross-sectional view of another embodiment where thecavities and pores are disposed in the surface 22′ of a stent strut. Asshown in FIG. 8, stent strut 50 has an abluminal surface 52 and aluminal surface 54. In this embodiment, stent strut 50 includes a metal,a metal oxide, ceramic oxide or inert carbon. The stent sidewallstructure 20′ of stent strut 50 also has a plurality of cavities 94 influid communication with the surface 52. The cavities 94 have a cavitysurface 96. Additionally, the stent strut includes a plurality of pores98, some of which are in fluid communication with a cavity surface 96.As shown in this embodiment, disposed within some of the pores 98 is afirst composition comprising or including a therapeutic agent 100.

Additionally, embodiments of the present invention wherein the cavitiesand pores are disposed in the surface of the stent can also includecoating compositions that include a therapeutic agent, a polymer, orboth a therapeutic agent and a polymer like those described in FIGS.2-7.

In accordance with the present invention, the cavities can have anyshape. For example, the cavities can be shaped like cylinders orhemispheres. Cavities can also have non-circular cross-sectional shapes.Cavities can also be shaped like conduits, channels or void pathways. Incertain embodiments the cavities can have cross-sectional shapes thatare narrow at the top, near the exposed surface of the coating and thenbecome broader near the surface of the medical device. Varying the shapecan be used to maximize or optimize the surface area of the cavitysurface which will determine the number of pores that can be in fluidcommunication with the cavity wall. Cavities having a cavity surfacewith a greater surface area will allow for a greater number of pores tobe in fluid communication with the cavity surface. A greater number ofpores will allow a greater amount of therapeutic agent to be loaded ontothe medical device.

The cavities can be any size that will allow a sufficient number ofpores to be formed in the cavity surface. For example, the cavities canbe about 0.1 microns to about 20 microns in diameter or width.Preferably, the cavities can be about 1 micron to about 10 microns indiameter or width. Additionally, the cavities can be about 0.1 micronsto about 20 microns deep. Preferably, the cavities can be about 1 micronto about 10 microns deep. In certain embodiments the cavities can be influid communication with the exposed surface of the medical device.Alternatively, in other embodiments the cavities may not be in fluidcommunication with the exposed surface of the medical device. Some orall of the cavities can be interconnected to other cavities.

Additionally, the pores can have any shape. For example, the pores canbe shaped like cylinders, spheres or hemispheres. Pores can also havenon-circular cross-sectional shapes. Pores can also be shaped likeconduits, channels or void pathways. Varying the shape of the pores canbe used to maximize or optimize that amount of therapeutic agent thatcan be loaded onto the surface of the medical device as well as the rateof release of the therapeutic agent. For example, pores having a largerwidth will allow the therapeutic agent to be released more quickly thanpores with a smaller width. Also, the number of pores can be adjusted tocontrol the release rate of the therapeutic agent. For example, thepresence of more pores per unit area of the cavity surface or unitvolume of the first coating material can increase the release rate ofthe therapeutic agent.

The pores are preferably smaller in size than the cavities and can beany size so long as at least some of the pores can be disposed on thecavity surface. For example, the pores can be about 0.001 microns toabout 10 microns in diameter or width. Preferably, the pores can beabout 0.01 microns to about 0.05 microns in diameter or width.Additionally, the pores can be about 0.001 microns to about 10 micronsdeep. Preferably, the pores can be about 0.01 microns to about 0.05microns deep. In certain embodiments, some of the pores can be in fluidcommunication with the surface of the medical device and the cavitysurface. Alternatively, in other embodiments the pores may not be influid communication with the surface of the medical device. Some or allof the pores can be interconnected to other pores.

A. Medical Devices

Suitable medical devices for the present invention include, but are notlimited to, stents, surgical staples, cochlear implants, catheters, suchas central venous catheters and arterial catheters, guidewires,cannulas, cardiac pacemaker leads or lead tips, cardiac defibrillatorleads or lead tips, implantable vascular access ports, blood storagebags, blood tubing, vascular or other grafts, intra-aortic balloonpumps, heart valves, cardiovascular sutures, total artificial hearts andventricular assist pumps, extra-corporeal devices such as bloodoxygenators, blood filters, hemodialysis units, hemoperfusion units orplasmapheresis units.

Medical devices which are particularly suitable for the presentinvention include any stent for medical purposes, which are known to theskilled artisan. Suitable stents include, for example, vascular stentssuch as self-expanding stents and balloon expandable stents. Examples ofself-expanding stents are illustrated in U.S. Pat. Nos. 4,655,771 and4,954,126 issued to Wallsten and 5,061,275 issued to Wallsten et al.Examples of appropriate balloon-expandable stents are shown in U.S. Pat.No. 5,449,373 issued to Pinchasik et al. In preferred embodiments, thestent suitable for the present invention is an Express stent. Morepreferably, the Express stent is an Express™ stent or an Express2™ stent(Boston Scientific, Inc. Natick, Mass.).

The framework of the suitable stents may be formed through variousmethods as known in the art. The framework may be welded, molded, lasercut, electro-formed, or consist of filaments or fibers which are woundor braided together in order to form a continuous structure.

Medical devices that are suitable for the present invention may befabricated from metallic, ceramic, polymeric or composite materials or acombination thereof. Preferably, the materials are biocompatible.Metallic material is more preferable. Suitable metallic materialsinclude metals and alloys based on titanium (such as nitinol, nickeltitanium alloys, thermo-memory alloy materials); stainless steel;tantalum, nickel-chrome; or certain cobalt alloys includingcobalt-chromium-nickel alloys such as Elgiloy® and Phynox®; PERSS(Platinum EnRiched Stainless Steel) and Niobium. Metallic materials alsoinclude clad composite filaments, such as those disclosed in WO94/16646.

Suitable ceramic materials include, but are not limited to, oxides,carbides, or nitrides of the transition elements such as titanium,hafnium, iridium, chromium, aluminum, and zirconium. Silicon basedmaterials, such as silica, may also be used.

Suitable polymers for forming the medical devices may be biostable.Also, the polymer may be biodegradable. Suitable polymers include, butare not limited to, styrene isobutylene styrene, polyetheroxides,polyvinyl alcohol, polyglycolic acid, polylactic acid, polyamides,poly-2-hydroxy-butyrate, polycaprolactone, polylactic-co-glycolic acid,and Teflon.

Polymers may be used for forming the medical device in the presentinvention include without limitation isobutylene-based polymers,polystyrene-based polymers, polyacrylates, and polyacrylate derivatives,vinyl acetate-based polymers and its copolymers, polyurethane and itscopolymers, silicone and its copolymers, ethylene vinyl-acetate,polyethylene terephtalate, thermoplastic elastomers, polyvinyl chloride,polyolefins, cellulosics, polyamides, polyesters, polysulfones,polytetrafluorethylenes, polycarbonates, acrylonitrile butadiene styrenecopolymers, acrylics, polylactic acid, polyglycolic acid,polycaprolactone, polylactic acid-polyethylene oxide copolymers,cellulose, collagens, and chitins.

Other polymers that are useful as materials for medical devices includewithout limitation dacron polyester, poly(ethylene terephthalate),polycarbonate, polymethylmethacrylate, polypropylene, polyalkyleneoxalates, polyvinylchloride, polyurethanes, polysiloxanes, nylons,poly(dimethyl siloxane), polycyanoacrylates, polyphosphazenes,poly(amino acids), ethylene glycol I dimethacrylate, poly(methylmethacrylate), poly(2-hydroxyethyl methacrylate),polytetrafluoroethylene poly(HEMA), polyhydroxyalkanoates,polytetrafluorethylene, polycarbonate, poly(glycolide-lactide)co-polymer, polylactic acid, poly(γ-caprolactone),poly(γ-hydroxybutyrate), polydioxanone, poly(γ-ethyl glutamate),polyiminocarbonates, poly(ortho ester), polyanhydrides, alginate,dextran, chitin, cotton, polyglycolic acid, polyurethane, or derivatizedversions thereof, i.e., polymers which have been modified to include,for example, attachment sites or cross-linking groups, e.g., RGD, inwhich the polymers retain their structural integrity while allowing forattachment of cells and molecules, such as proteins, nucleic acids, andthe like.

Medical devices may also be made with non-polymers. Examples of usefulnon-polymers include sterols such as cholesterol, stigmasterol,β-sitosterol, and estradiol; cholesteryl esters such as cholesterylstearate; C₁₂-C₂₄ fatty acids such as lauric acid, myristic acid,palmitic acid, stearic acid, arachidic acid, behenic acid, andlignoceric acid; C₁₈-C₃₆ mono-, di- and triacylglycerides such asglyceryl monooleate, glyceryl monolinoleate, glyceryl monolaurate,glyceryl monodocosanoate, glyceryl monomyristate, glycerylmonodicenoate, glyceryl dipalmitate, glyceryl didocosanoate, glyceryldimyristate, glyceryl didecenoate, glyceryl tridocosanoate, glyceryltrimyristate, glyceryl tridecenoate, glycerol tristearate and mixturesthereof; sucrose fatty acid esters such as sucrose distearate andsucrose palmitate; sorbitan fatty acid esters such as sorbitanmonostearate, sorbitan monopalmitate and sorbitan tristearate; C₁₆-C₁₈fatty alcohols such as cetyl alcohol, myristyl alcohol, stearyl alcohol,and cetostearyl alcohol; esters of fatty alcohols and fatty acids suchas cetyl palmitate and cetearyl palmitate; anhydrides of fatty acidssuch as stearic anhydride; phospholipids including phosphatidylcholine(lecithin), phosphatidylserine, phosphatidylethanolamine,phosphatidylinositol, and lysoderivatives thereof; sphingosine andderivatives thereof; sphingomyelins such as stearyl, palmitoyl, andtricosanyl sphingomyelins; ceramides such as stearyl and palmitoylceramides; glycosphingolipids; lanolin and lanolin alcohols; andcombinations and mixtures thereof. Non-polymers may also includebiomaterials such as stem sells, which can be seeded into the medicaldevice prior to implantation. Preferred non-polymers includecholesterol, glyceryl monostearate, glycerol tristearate, stearic acid,stearic anhydride, glyceryl monooleate, glyceryl monolinoleate, andacetylated monoglycerides.

B. Coating Composition Materials

Metals, Metal Oxides, Ceramic Oxides and Carbons

When the first coating composition comprises a plurality of cavities anda plurality of pores, the first coating composition can include a metal,a metal oxide, ceramic oxide or inert carbon. The first coatingcomposition can also be radiopaque and/or have MRI compatibility. Also,the first coating composition can have the same or some of the samematerials that are used to make the medical device, specifically themedical device surface, on which the first coating composition isapplied to.

Suitable metals include, but are not limited to, alkali metals, alkalineearth metals, transition metals, metal alloys and metalloids. Examplesof metals include, but are not limited to, titanium, scandium, stainlesssteel, tantalum, nickel, Nitinol, chrome, cobalt, chromium, manganese,iron, platinum, iridium, niobium, vanadium, zirconium, tungsten,rhodium, ruthenium, gold, copper, zinc, yttrium, molybdenum, technetium,palladium, cadmium, hafnium, rhenium and combinations thereof. Incertain embodiments, preferred metals include without limitation, goldtantalum, platinum, titanium, Nitinol or a combination thereof.

Suitable metal oxides and ceramic oxides include but are not limited to,platinum oxides, tantalum oxides, titanium oxides, zinc oxides, ironoxides, magnesium oxides, aluminum oxides, iridium oxides, niobiumoxides, zirconium oxides, tungsten oxides, rhodium oxides, rutheniumoxides, hydroxyapatite, calcium phosphates, alumina, zirconia,zirconium, silicone oxides such as silica based glasses and silicondioxide, or combinations thereof. In certain embodiments, preferredmetal oxides or ceramic oxides include without limitation, iridiumoxide, titanium oxide, titanium dioxide, iron oxide, hydroxyapatite,calcium phosphates, alumina, zirconia, zirconium, silica based glasses,or a combination thereof.

In other embodiments, the first coating composition can include inertcarbon. Suitable forms of inert carbon can include with out limitation,pyrolitic carbon, porous vitreous carbon, diamond-like carbon, graphiteand physical vapor deposition (PVD) carbon. Use of porous carbon canhelp prevent thrombosis and encourage endothelial cell growth.

In some embodiments, the metal, metal oxide, ceramic oxide or inertcarbon can comprise at least 5%, at least 10%, at least 20%, at least30%, at least 40%, at least 50%, at least 60%, at least 70%, at least80%, at least 90%, at least 95%, at least 97%, at least 99% or more byweight of the coating composition. Preferably, the metal, metal oxide,ceramic oxide or inert carbon is about 10% to about 70% by weight of thecoating composition.

The first coating composition may be of any thickness. In someembodiments, the first coating composition preferably has a thickness ofabout 1 to about 30 microns. In some instances, a relatively thickerfilm may be preferred to incorporate deeper cavities with more cavitysurface.

Therapeutic Agents

The term “therapeutic agent” as used in the present inventionencompasses therapeutic agents, genetic materials, and biologicalmaterials and can be used interchangeably with “biologically activematerial”. In one embodiment, the therapeutic agent is ananti-restenotic agent. In other embodiments, the therapeutic agentinhibits smooth muscle cell proliferation, contraction, migration orhyperactivity. Non-limiting examples of suitable therapeutic agentinclude heparin, heparin derivatives, urokinase, dextrophenylalanineproline arginine chloromethylketone (PPack), enoxaprin, angiopeptin,hirudin, acetylsalicylic acid, tacrolimus, everolimus, zotarolimus,rapamycin (sirolimus), pimecrolimus, zotarolimus, amlodipine, doxazosin,glucocorticoids, betamethasone, dexamethasone, prednisolone,corticosterone, budesonide, sulfasalazine, rosiglitazone, mycophenolicacid, mesalamine, paclitaxel, 5-fluorouracil, cisplatin, vinblastine,vincristine, epothilones, methotrexate, azathioprine, adriamycin,mutamycin, endostatin, angiostatin, thymidine kinase inhibitors,cladribine, lidocaine, bupivacaine, ropivacaine, D-Phe-Pro-Argchloromethyl ketone, platelet receptor antagonists, anti-thrombinantibodies, anti-platelet receptor antibodies, aspirin, dipyridamole,protamine, hirudin, prostaglandin inhibitors, platelet inhibitors,trapidil, liprostin, tick antiplatelet peptides, 5-azacytidine, vascularendothelial growth factors, growth factor receptors, transcriptionalactivators, translational promoters, antiproliferative agents, growthfactor inhibitors, growth factor receptor antagonists, transcriptionalrepressors, translational repressors, replication inhibitors, inhibitoryantibodies, antibodies directed against growth factors, bifunctionalmolecules consisting of a growth factor and a cytotoxin, bifunctionalmolecules consisting of an antibody and a cytotoxin, cholesterollowering agents, vasodilating agents, agents which interfere withendogenous vasoactive mechanisms, antioxidants, probucol, antibioticagents, penicillin, cefoxitin, oxacillin, tobranycin, angiogenicsubstances, fibroblast growth factors, estrogen, estradiol (E2), estriol(E3), 17-beta estradiol, digoxin, beta blockers, captopril, enalopril,statins, steroids, vitamins, paclitaxel (as well as its derivatives,analogs or paclitaxel bound to proteins, e.g. Abraxane™)2′-succinyl-taxol, 2′-succinyl-taxol triethanolamine, 2′-glutaryl-taxol,2′-glutaryl-taxol triethanolamine salt, 2′-O-ester withN-(dimethylaminoethyl) glutamine, 2′-O-ester with N-(dimethylaminoethyl)glutamide hydrochloride salt, nitroglycerin, nitrous oxides, nitricoxides, antibiotics, aspirins, digitalis, estrogen, estradiol andglycosides. In one embodiment, the therapeutic agent is a smooth musclecell inhibitor or antibiotic. In a preferred embodiment, the therapeuticagent is taxol (e.g., Taxol®), or its analogs or derivatives. In anotherpreferred embodiment, the therapeutic agent is paclitaxel, (i.e.paclitaxel, its analogs or derivatives). In yet another preferredembodiment, the therapeutic agent is an antibiotic such as erythromycin,amphotericin, rapamycin, adriamycin, etc.

The term “genetic materials” means DNA or RNA, including, withoutlimitation, of DNA/RNA encoding a useful protein stated below, intendedto be inserted into a human body including viral vectors and non-viralvectors.

The term “biological materials” include cells, yeasts, bacteria,proteins, peptides, cytokines and hormones. Examples for peptides andproteins include vascular endothelial growth factor (VEGF), transforminggrowth factor (TGF), fibroblast growth factor (FGF), epidermal growthfactor (EGF), cartilage growth factor (CGF), nerve growth factor (NGF),keratinocyte growth factor (KGF), skeletal growth factor (SGF),osteoblast-derived growth factor (BDGF), hepatocyte growth factor (HGF),insulin-like growth factor (IGF), cytokine growth factors (CGF),platelet-derived growth factor (PDGF), hypoxia inducible factor-1(HIF-1), stem cell derived factor (SDF), stem cell factor (SCF),endothelial cell growth supplement (ECGS), granulocyte macrophage colonystimulating factor (GM-CSF), growth differentiation factor (GDF),integrin modulating factor (IMF), calmodulin (CaM), thymidine kinase(TK), tumor necrosis factor (TNF), growth hormone (GH), bone morphogenicprotein (BMP) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7(PO-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-14, BMP-15, BMP-16,etc.), matrix metalloproteinase (MMP), tissue inhibitor of matrixmetalloproteinase (TIMP), cytokines, interleukin (e.g., IL-1, IL-2,IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-15,etc.), lymphokines, interferon, integrin, collagen (all types), elastin,fibrillins, fibronectin, vitronectin, laminin, glycosaminoglycans,proteoglycans, transferrin, cytotactin, cell binding domains (e.g.,RGD), and tenascin. Currently preferred BMP's are BMP-2, BMP-3, BMP-4,BMP-5, BMP-6, BMP-7. These dimeric proteins can be provided ashomodimers, heterodimers, or combinations thereof, alone or togetherwith other molecules. Cells can be of human origin (autologous orallogeneic) or from an animal source (xenogeneic), geneticallyengineered, if desired, to deliver proteins of interest at thetransplant site. The delivery media can be formulated as needed tomaintain cell function and viability. Cells include progenitor cells(e.g., endothelial progenitor cells), stem cells (e.g., mesenchymal,hematopoietic, neuronal), stromal cells, parenchymal cells,undifferentiated cells, fibroblasts, macrophage, and satellite cells.

Other non-genetic therapeutic agents include:

-   -   anti-thrombogenic agents such as heparin, heparin derivatives,        urokinase, and PPack (dextrophenylalanine proline arginine        chloromethylketone);    -   anti-proliferative agents such as enoxaprin, angiopeptin, or        monoclonal antibodies capable of blocking smooth muscle cell        proliferation, hirudin, acetylsalicylic acid, tacrolimus,        everolimus, amlodipine and doxazosin;    -   anti-inflammatory agents such as glucocorticoids, betamethasone,        dexamethasone, prednisolone, corticosterone, budesonide,        estrogen, sulfasalazine, rosiglitazone, mycophenolic acid and        mesalamine;    -   anti-neoplastic/anti-proliferative/anti-miotic agents such as        paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine,        epothilones, methotrexate, azathioprine, adriamycin and        mutamycin; endostatin, angiostatin and thymidine kinase        inhibitors, cladribine, taxol and its analogs or derivatives;    -   anesthetic agents such as lidocaine, bupivacaine, and        ropivacaine;    -   anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, an        RGD peptide-containing compound, heparin, antithrombin        compounds, platelet receptor antagonists, anti-thrombin        antibodies, anti-platelet receptor antibodies, aspirin (aspirin        is also classified as an analgesic, antipyretic and        anti-inflammatory therapeutic agent), dipyridamole, protamine,        hirudin, prostaglandin inhibitors, platelet inhibitors,        antiplatelet agents such as trapidil or liprostin and tick        antiplatelet peptides;    -   DNA demethylating therapeutic agents such as 5-azacytidine,        which is also categorized as a RNA or DNA metabolite that        inhibit cell growth and induce apoptosis in certain cancer        cells;    -   vascular cell growth promoters such as growth factors, vascular        endothelial growth factors (VEGF, all types including VEGF-2),        growth factor receptors, transcriptional activators, and        translational promoters;    -   vascular cell growth inhibitors such as anti-proliferative        agents, growth factor inhibitors, growth factor receptor        antagonists, transcriptional repressors, translational        repressors, replication inhibitors, inhibitory antibodies,        antibodies directed against growth factors, bifunctional        molecules consisting of a growth factor and a cytotoxin,        bifunctional molecules consisting of an antibody and a        cytotoxin;    -   cholesterol-lowering agents, vasodilating agents, and agents        which interfere with endogenous vasoactive mechanisms;    -   anti-oxidants, such as probucol;    -   antibiotic agents, such as penicillin, cefoxitin, oxacillin,        tobranycin, rapamycin (sirolimus);    -   angiogenic substances, such as acidic and basic fibroblast        growth factors, estrogen including estradiol (E2), estriol (E3)        and 17-beta estradiol; therapeutic agents for heart failure,        such as digoxin, beta-blockers, angiotensin-converting enzyme        (ACE) inhibitors including captopril and enalopril, statins and        related compounds; and    -   macrolides such as sirolimus, everolimus, tacrolimus,        pimecrolimus or zotarolimus.

Preferred biological materials include anti-proliferative therapeuticagents such as steroids, vitamins, and restenosis-inhibiting agents.Preferred restenosis-inhibiting agents include microtubule stabilizingagents such as Taxol®, paclitaxel (i.e., paclitaxel, paclitaxel analogs,or paclitaxel derivatives, and mixtures thereof). For example,derivatives suitable for use in the present invention include2′-succinyl-taxol, 2′-succinyl-taxol triethanolamine, 2′-glutaryl-taxol,2′-glutaryl-taxol triethanolamine salt, 2′-O-ester withN-(dimethylaminoethyl) glutamine, and 2′-O-ester withN-(dimethylaminoethyl) glutamide hydrochloride salt.

Other suitable therapeutic agents include tacrolimus; halofuginone;inhibitors of HSP90 heat shock proteins such as geldanamycin;microtubule stabilizing agents such as epothilone D; phosphodiesteraseinhibitors such as cliostazole; Barkct inhibitors; phospholambaninhibitors; and Serca 2 gene/proteins.

Other preferred therapeutic agents include nitroglycerin, nitrousoxides, nitric oxides, aspirins, digitalis, estrogen derivatives such asestradiol and glycosides.

In one embodiment, the therapeutic agent is capable of altering thecellular metabolism or inhibiting a cell activity, such as proteinsynthesis, DNA synthesis, spindle fiber formation, cellularproliferation, cell migration, microtubule formation, microfilamentformation, extracellular matrix synthesis, extracellular matrixsecretion, or increase in cell volume. In another embodiment, thetherapeutic agent is capable of inhibiting cell proliferation and/ormigration.

In certain embodiments, the therapeutic agents for use in the medicaldevices of the present invention can be synthesized by methods wellknown to one skilled in the art. Alternatively, the therapeutic agentscan be purchased from chemical and pharmaceutical companies.

In certain embodiments, when the cavities and pores are disposed in acoating composition, the therapeutic agent comprises at least 5%, atleast 10%, at least 20%, at least 30%, at least 40%, at least 50%, atleast 60%, at least 70%, at least 80%, at least 90%, at least 95%, atleast 97%, at least 99% or more by weight of the coating composition.Preferably, the therapeutic agent is about 5% to about 35% by weight ofthe coating composition. More preferably, the therapeutic agent is about8% to about 20% by weight of the second or third coating composition.

In other embodiments, when the cavities and pores are disposed in thestent, the therapeutic agent comprises at least 5%, at least 10%, atleast 20%, at least 30%, at least 40%, at least 50%, at least 60%, atleast 70%, at least 80%, at least 90%, at least 95%, at least 97%, atleast 99% or more by weight of the composition. Preferably, thetherapeutic agent is about 5% to about 35% by weight of the first orsecond composition. More preferably, the therapeutic agent is about 8%to about 20% percent by weight of the composition.

Polymers

Polymers useful in the present invention should be ones that arebiocompatible, particularly during insertion or implantation of thedevice into the body and avoids irritation to body tissue. Examples ofsuch polymers include, but not limited to, polyurethanes,polyisobutylene and its copolymers, silicones, and polyesters. Othersuitable polymers include polyolefins, polyisobutylene,ethylene-alphaolefin copolymers, acrylic polymers and copolymers, vinylhalide polymers and copolymers such as polyvinyl chloride, polyvinylethers such as polyvinyl methyl ether, polyvinylidene halides such aspolyvinylidene fluoride and polyvinylidene chloride, polyacrylonitrile,polyvinyl ketones, polyvinyl aromatics such as polystyrene, polyvinylesters such as polyvinyl acetate; copolymers of vinyl monomers,copolymers of vinyl monomers and olefins such as ethylene-methylmethacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins,ethylene-vinyl acetate copolymers, polyamides such as Nylon 66 andpolycaprolactone, alkyd resins, polycarbonates, polyoxyethylenes,polyimides, polyethers, epoxy resins, polyurethanes, rayon-triacetate,cellulose, cellulose acetate, cellulose butyrate, cellulose acetatebutyrate, cellophane, cellulose nitrate, cellulose propionate, celluloseethers, carboxymethyl cellulose, collagens, chitins, polylactic acid,polyglycolic acid, and polylactic acid-polyethylene oxide copolymers.

In certain embodiment hydrophobic polymers can be used. Examples ofsuitable hydrophobic polymers or monomers include, but not limited to,polyolefins, such as polyethylene, polypropylene, poly(1-butene),poly(2-butene), poly(1-pentene), poly(2-pentene),poly(3-methyl-1-pentene), poly(4-methyl-1-pentene), poly(isoprene),poly(4-methyl-1-pentene), ethylene-propylene copolymers,ethylene-propylene-hexadiene copolymers, ethylene-vinyl acetatecopolymers, blends of two or more polyolefins and random and blockcopolymers prepared from two or more different unsaturated monomers;styrene polymers, such as poly(styrene), poly(2-methylstyrene),styrene-acrylonitrile copolymers having less than about 20 mole-percentacrylonitrile, and styrene-2,2,3,3-tetrafluoropropyl methacrylatecopolymers; halogenated hydrocarbon polymers, such aspoly(chlorotrifluoroethylene),chlorotrifluoroethylene-tetrafluoroethylene copolymers,poly(hexafluoropropylene), poly(tetrafluoroethylene),tetrafluoroethylene, tetrafluoroethylene-ethylene copolymers,poly(trifluoroethylene), poly(vinyl fluoride), and poly(vinylidenefluoride); vinyl polymers, such as poly(vinyl butyrate), poly(vinyldecanoate), poly(vinyl dodecanoate), poly(vinyl hexadecanoate),poly(vinyl hexanoate), poly(vinyl propionate), poly(vinyl octanoate),poly(heptafluoroisopropoxyethylene),poly(heptafluoroisopropoxypropylene), and poly(methacrylonitrile);acrylic polymers, such as poly(n-butyl acetate), poly(ethyl acrylate),poly(1-chlorodifluoromethyl)tetrafluoroethyl acrylate, polydi(chlorofluoromethyl)fluoromethyl acrylate,poly(1,1-dihydroheptafluorobutyl acrylate),poly(1,1-dihydropentafluoroisopropyl acrylate),poly(1,1-dihydropentadecafluorooctyl acrylate),poly(heptafluoroisopropyl acrylate), poly5-(heptafluoroisopropoxy)pentyl acrylate, poly11-(heptafluoroisopropoxy)undecyl acrylate, poly2-(heptafluoropropoxy)ethyl acrylate, and poly(nonafluoroisobutylacrylate); methacrylic polymers, such as poly(benzyl methacrylate),poly(n-butyl methacrylate), poly(isobutyl methacrylate), poly(t-butylmethacrylate), poly(t-butylaminoethyl methacrylate), poly(dodecylmethacrylate), poly(ethyl methacrylate), poly(2-ethylhexylmethacrylate), poly(n-hexyl methacrylate), poly(phenyl methacrylate),poly(n-propyl methacrylate), poly(octadecyl methacrylate),poly(1,1-dihydropentadecafluorooctyl methacrylate),poly(heptafluoroisopropyl methacrylate), poly(heptadecafluorooctylmethacrylate), poly(1-hydrotetrafluoroethyl methacrylate),poly(1,1-dihydrotetrafluoropropyl methacrylate),poly(1-hydrohexafluoroisopropyl methacrylate), andpoly(t-nonafluorobutyl methacrylate); polyesters, such a poly(ethyleneterephthalate) and poly(butylene terephthalate); condensation typepolymers such as and polyurethanes and siloxane-urethane copolymers;polyorganosiloxanes, i.e., polymers characterized by repeating siloxanegroups, represented by Ra SiO 4-a/2, where R is a monovalent substitutedor unsubstituted hydrocarbon radical and the value of a is 1 or 2; andnaturally occurring hydrophobic polymers such as rubber.

In alternative embodiments, hydrophilic polymers can be used. Examplesof suitable hydrophilic polymers or monomers include, but not limitedto; (meth)acrylic acid, or alkaline metal or ammonium salts thereof;(meth)acrylamide; (meth)acrylonitrile; those polymers to whichunsaturated dibasic, such as maleic acid and fumaric acid or half estersof these unsaturated dibasic acids, or alkaline metal or ammonium saltsof these dibasic adds or half esters, is added; those polymers to whichunsaturated sulfonic, such as 2-acrylamido-2-methylpropanesulfonic,2-(meth)acryloylethanesulfonic acid, or alkaline metal or ammonium saltsthereof, is added; and 2-hydroxyethyl (meth)acrylate and 2-hydroxypropyl(meth)acrylate.

Polyvinyl alcohol is also an example of hydrophilic polymer. Polyvinylalcohol may contain a plurality of hydrophilic groups such as hydroxyl,amido, carboxyl, amino, ammonium or sulfonyl (—SO₃). Hydrophilicpolymers also include, but are not limited to, starch, polysaccharidesand related cellulosic polymers; polyalkylene glycols and oxides such asthe polyethylene oxides; polymerized ethylenically unsaturatedcarboxylic acids such as acrylic, mathacrylic and maleic acids andpartial esters derived from these acids and polyhydric alcohols such asthe alkylene glycols; homopolymers and copolymers derived fromacrylamide; and homopolymers and copolymers of vinylpyrrolidone.

Additional suitable polymers include, but are not limited to,thermoplastic elastomers in general, polyolefins, polyisobutylene,ethylene-alphaolefin copolymers, acrylic polymers and copolymers, vinylhalide polymers and copolymers such as polyvinyl chloride, polyvinylethers such as polyvinyl methyl ether, polyvinylidene halides such aspolyvinylidene fluoride and polyvinylidene chloride, polyacrylonitrile,polyvinyl ketones, polyvinyl aromatics such as polystyrene, polyvinylesters such as polyvinyl acetate, copolymers of vinyl monomers,copolymers of vinyl monomers and olefins such as ethylene-methylmethacrylate copolymers, acrylonitrile-styrene copolymers, ABS(acrylonitrile-butadiene-styrene) resins, ethylene-vinyl acetatecopolymers, polyamides such as Nylon 66 and polycaprolactone, alkydresins, polycarbonates, polyoxymethylenes, polyimides, polyethers,polyether block amides, epoxy resins, rayon-triacetate, cellulose,cellulose acetate, cellulose butyrate, cellulose acetate butyrate,cellophane, cellulose nitrate, cellulose propionate, cellulose ethers,carboxymethyl cellulose, collagens, chitins, polylactic acid,polyglycolic acid, polylactic acid-polyethylene oxide copolymers, EPDM(ethylene-propylene-diene) rubbers, fluoropolymers, fluorosilicones,polyethylene glycol, polysaccharides, phospholipids, and combinations ofthe foregoing.

Other polymers which can be used include ones that can be easilydissolved in water or organic solvents, cured or polymerized in thecavities of the first coating composition, have relatively low meltingpoints and/or can be blended with therapeutic agents. Also bioabsorbablepolymers may be used wherein the therapeutic agent is release as thepolymer is absorbed into the body. An additional advantage of using abioabsorbable material is that once the polymer is absorbed, the emptycavities can help prevent thromboses and encourage endothelial cellgrowth.

In certain embodiments preferred polymers include, but are not limitedto, styrene-isobutylene-styrene, polylactic-co-glycolic acid (PLGA),polybutyl methacrylate (PBMA), polyvinylidene fluoride (PVDF), or acombination thereof.

C. Methods of Making the Coatings

In certain embodiments, the medical devices of the present invention aremade by a method that includes the steps of disposing a first coatingcomposition on at least a portion of a surface of a medical devicewherein the first coating composition includes a metal, metal oxide,ceramic oxide or inert carbon; forming a plurality of cavities in thefirst coating composition, wherein the cavities have a cavity surface;forming a plurality of pores within the cavity surface; and disposing asecond coating composition in the pores wherein the second coatingcomposition includes a therapeutic agent.

In other embodiments, the medical device coatings of the presentinvention can be made by a method including the steps of disposing afirst coating composition on at least a portion of a surface of amedical device wherein the first coating composition includes a metal,metal oxide, ceramic oxide or inert carbon; forming a plurality of poreswithin the first coating composition; thereafter forming a plurality ofcavities in the first coating composition, wherein the cavities have acavity surface and wherein at least some of the pores are in fluidcommunication with at least a cavity surface; and disposing a secondcoating composition in the pores wherein the second coating compositionincludes a therapeutic agent.

In the above methods, the first coating composition can be disposed onat least a portion of the surface of the medical device by any suitablemethod such as, but not limited to, dipping, spraying, painting,electroplating, evaporation, plasma vapor deposition, physical vapordeposition, cathodic-arc deposition, sputtering, ion implantation,electrostatically, electrochemically or a combination thereof.

The cavities and/or the pores in the first coating composition can beformed by any method known in the art as well. These methods include,but are not limited to, laser ablation, drilling, or chemical etching,microcontact printing, inkjet printing, screen printing, replicamolding, microtransfer molding, micromolding in capillaries,solvent-assisted micromolding, proximal probe lithography,photolithography, scanning probe lithography, and embossing techniques.

Additionally, cavities and/or the pores in the first coating compositioncan be formed by removing a secondary material from the first coatingcomposition. Techniques for removing a secondary material include, butare not limited to, dealloying or anodization processes. For example, afirst coating composition containing a secondary material is disposed ona portion of a surface of a medical device. The first coatingcomposition comprises a metal, metal oxide, ceramic oxide or inertcarbon. The secondary material can be any material so long as it can beremoved from the first coating composition. For example, the secondarymaterial can be more electrochemically active than other metals in thecoating composition. Preferably, the secondary material is a metal.Suitable metals include, but are not limited to, silver, gold, tantalum,platinum, bismuth, iridium, zirconium, iodine, titanium, and barium.After the first coating composition with the secondary material isdisposed on the surface of the medical device, a plurality of cavitiesand/or pores are formed in the first coating composition by removing thesecondary material.

The secondary material can be removed from the first coating compositionby a dealloying process such as selective dissolution of the secondarymaterial. In this method, the first coating composition and thesecondary material are exposed to an acid which removes the secondarymetal. Thus, the first coating composition is preferably one that willnot dissolve when exposed to the acid, while the secondary metal is onethat will dissolve. Any suitable acid can be used to remove the secondmetal. One of ordinary skill in the art would recognize the appropriateconcentration and reaction conditions to use to remove the second metal.For example, if the secondary material is silver, nitric acid may beused at a concentration of up to 35% and a temperature up to 120° F.Also, a nitric acid and sulfuric acid mixture (95%/5%) immersion processat 80° F. may be used. The reaction conditions may be varied to vary thegeometry, distribution, and depth of the coating layer.

Alternatively, the secondary material can be removed anodically. Forexample, silver may be removed anodically using a dilute nitric acidbath comprising up to 15% nitric acid, wherein the anode is the platedstent, and the cathode is platinum. Voltages up to 10V DC can be appliedacross the electrodes. The bath chemistry, temperature, applied voltage,and process time may be varied to vary the geometry, distribution, anddepth of the coating layer. In another example, a Technic Envirostrip Ag10-20 amps per square foot may be used with a stainless steel cathode.

In another embodiment, the present invention includes a method ofcoating a medical device that includes the steps of masking a portion ofa surface of a medical device, such as a stent, with a masking material;disposing a first coating composition on the surface of the medicaldevice, wherein the first coating composition includes a metal, metaloxide, ceramic oxide or inert carbon; forming a plurality of pores inthe first coating composition; removing the masking material, creating aplurality of cavities; and disposing a second coating composition in thepores wherein, the second coating composition comprises a therapeuticagent.

For example, before the first coating composition is disposed on aportion of the surface of the medical device, polymer droplets can beapplied to a portion of a surface of a medical device to mask theportion of the surface which that will comprise the cavities. Thepolymer droplets can be applied by methods such as inkjet printing andlithography. Once the first coating composition is disposed on thesurface of the medical device, the polymer is removed, forming aplurality of cavities.

In the embodiments where the first coating composition includes cavitiesand pores, a second coating composition can be disposed in the pores.The second coating composition can include a therapeutic agent.Alternatively, the second coating composition can further include apolymer. The second coating composition can be disposed in the pores orcavities of the first coating composition in any suitable way known inthe art. Such methods include, but are not limited to, inkjet printingor vacuum impregnation. Additional methods include coating the medicaldevice with the second coating composition and removing the excess. Forexample, the second coating composition can be applied to a portion of asurface of a medical device by such methods as dipping, spraying,painting, roll coating, or a combination thereof and then removing theexcess.

To facilitate disposing the second coating composition within the pores,a solution or suspension can be formed by dissolving or suspending thetherapeutic agent in an organic or aqueous solvent, which is thendisposed in at least some of the pores and the solvent is removed.

The above methods can further include disposing the second coatingcomposition within at least some of the cavities. Alternatively, inother embodiments of the methods of the present invention, the methodscan further include disposing a third coating composition within thecavities. The third coating composition can include a second therapeuticagent, wherein the second therapeutic agent is the same or differenttherapeutic agent than the first therapeutic agent. Alternatively, thethird therapeutic agent can include a polymer or a polymer and a secondtherapeutic agent.

In general, when the coating compositions of the present inventionincludes polymer or a therapeutic agent and a polymer, a monomer can bemixed together and disposed in the pores and/or cavities with aninitiator. Once in the pores and/or cavities the monomer can bepolymerized by such methods as exposure to UV radiation or heat. Thedegree of polymerization, monomer and initiator used will be determinedby the desired rate of release of the therapeutic agent.

Also encompassed in the present invention are methods of making animplantable stent having a surface including a metal, a metal oxide,ceramic oxide or inert carbon, wherein the method includes the steps offorming a plurality of pores in the metal oxide, ceramic oxide or inertcarbon surface; forming a plurality of cavities in the metal, metaloxide, ceramic oxide or inert carbon surface, wherein the cavities havea cavity surface and wherein at least some of the pores are in fluidcommunication with the cavity surface; and disposing a first compositionhaving a first therapeutic agent within at least some of the pores.

Alternatively, in certain embodiments of the methods of the presentinvention include methods of making an implantable stent having asurface having a metal, a metal oxide, ceramic oxide or inert carbon,the method comprising forming a plurality of cavities in the metal,metal oxide, ceramic oxide or inert carbon surface, wherein the cavitieshave a cavity surface thereafter; forming a plurality of pores in themetal, metal oxide, ceramic oxide or inert carbon surface, wherein atleast some of the pores are in fluid communication with the cavitysurface; and disposing a first composition having a first therapeuticagent within at least some of the pores.

Cavities and pores can be formed in the metal, metal oxide, ceramicoxide or inert carbon surface of a stent by any methods known in theart. For example, the cavities and the pores can be formed by themethods used to form the cavities and pores in the first coatingcomposition discussed above.

Once cavities and pores are formed in the metal, metal oxide, ceramicoxide or inert carbon surface of the stent, a first composition can bedisposed in the pores. The first composition can include a therapeuticagent. Alternatively, the first composition can further include apolymer. The first composition can be disposed in the pores of thesurface of the stent in any suitable way known in the art. Such methodsinclude, but are not limited to, inkjet printing or vacuum impregnation.Additional methods include coating the medical device with the firstcomposition and removing the excess. For example, the first compositioncan be applied to a portion of a surface of a medical device by suchmethods as dipping, spraying, painting, roll coating, or a combinationthereof and then removing the excess.

To facilitate disposing the first composition within the pores in themetal, metal oxide, ceramic oxide or inert carbon surface of the sent, asolution or suspension can be formed by dissolving or suspending atherapeutic agent in an organic or aqueous solvent which is thendeposited in at least some of the pores and then the solvent is removed.The first composition can also be disposed within at least some of thecavities.

The medical devices and stents of the present invention may be used forany appropriate medical procedure. Delivery of the medical device can beaccomplished using methods well known to those skilled in the art.

The following examples are for purposes of illustration and not forpurposes of limitation.

EXAMPLE 1

A stainless steel stent is coated with a porous carbon coating havingpores of nanometer size. The coating is applied using a PVD process.Cavities are ablated in the carbon coating using a UV laser, excimer orDPSS laser focused to a small size (<10 microns). The stent is thensprayed with a solution of paclitaxel in a toluene/TFH solvent system.

The description contained herein is for purposes of illustration and notfor purposes of limitation. Changes and modifications may be made to theembodiments of the description and still be within the scope of theinvention. Furthermore, obvious changes, modifications or variationswill occur to those skilled in the art. Also, all references cited aboveare incorporated herein, in their entirety, for all purposes related tothis disclosure.

1. An implantable stent comprising: a stent sidewall structurecomprising (a) a stent strut body having a surface defined by the stentstrut body or by a surface coating on the stent strut body, the surfacecomprising a metal, a metal oxide, a ceramic oxide, or inert carbon; (b)the surface defining a plurality of cavities therein, at least some ofthe cavities being in fluid communication with the surface and at leastone cavity being defined by a cavity surface having a plurality of porestherein; (c) a second coating composition comprising a first therapeuticagent, wherein the second coating composition is disposed within aportion of at least one of the cavities; and (d) a cap disposed in theat least one of the cavities and covering the second coatingcomposition, wherein the cap is within the at least one of the cavitiesand wherein at least some of the pores in the cavity surface being notcovered by the cap and being in fluid communication with the surface,thereby causing the first therapeutic agent to release through the poresto the surface and to not substantially release from the cavity directlyto the surface.
 2. The implantable stent of claim 1, wherein: the stentsidewall structure comprises the stent strut body and the surfacecoating on the stent strut, the surface is a surface of the surfacecoating, and the cavities are defined by the surface coating.
 3. Thestent of claim 1, wherein the sidewall structure comprises a pluralityof struts and openings in the sidewall structure.
 4. The stent of claim2, wherein the surface is on an abluminal side of the stent strut body.5. The stent of claim 3, wherein the surface coating conforms to asurface of the stent strut body so that the openings of the stentsidewall structure are preserved, and wherein the surface of thesidewall structure comprises an abluminal surface.
 6. The stent of claim1, wherein the stent is an intravascular balloon-expandable stent. 7.The stent of claim 1, wherein the stent is an intravascularself-expanding stent.
 8. The stent of claim 2, wherein the surfacecoating composition is radiopaque.
 9. The stent of claim 2, wherein thesurface coating composition is free of any polymer.
 10. The stent ofclaim 2, wherein the pores are distributed throughout the surfacecoating.
 11. The stent of claim 10, wherein the pores are homogenouslydistributed throughout the surface coating.
 12. The stent of claim 1,wherein the second coating composition is also disposed within at leastone of the pores.
 13. The stent of claim 1, wherein the second coatingcomposition further comprises a polymer.
 14. The stent of claim 13,wherein the polymer is biostable.
 15. The stent of claim 13, wherein thepolymer is bioabsorbable.
 16. The stent of claim 13, wherein the polymercomprises styrene-isobutylene-styrene, polylactic-co-glycolic acid(PLGA), polybutyl methacrylate (PBMA), polyvinylidene fluoride (PVDF),or a combination thereof.
 17. The stent of claim 1, wherein the metaloxide or ceramic oxide comprises iridium oxide, titanium oxide, titaniumdioxide, iron oxide, hydroxyapatite, calcium phosphates, alumina,zirconia, zirconium, silica based glasses, or a combination thereof. 18.The stent of claim 1, wherein the metal comprises gold, tantalum,platinum, titanium, Nitinol or a combination thereof.
 19. The stent ofclaim 1, wherein the surface coating is about 1 micron to about 30microns thick.
 20. The stent of claim 1, wherein the diameter of thepores is less than or equal to one micron.
 21. The stent of claim 1,wherein the width of the cavities is greater than or equal to onemicron.
 22. The stent of claim 1, wherein the stent sidewall structurefurther comprises a third coating composition comprising a secondtherapeutic agent and, wherein the third coating composition is disposedwithin the pores.
 23. The stent of claim 22, wherein the firsttherapeutic agent and second therapeutic agent are different.
 24. Thestent of claim 1, wherein the first therapeutic agent comprises ananti-thrombogenic agent, anti-angiogenesis agent, anti-proliferativeagent, antibiotic, anti-restenosis agent, growth factor,immunosuppressant, or radiochemical.
 25. The stent of claim 1, whereinthe first therapeutic agent comprises an anti-restenosis agent.
 26. Thestent of claim 1, wherein the first therapeutic agent comprisespaclitaxel.
 27. The stent of claim 1, wherein the first therapeuticagent comprises sirolimus, tacrolimus, pimecrolimus, zotarolimus, oreverolimus.
 28. The stent of claim 1, wherein the cap comprises apolymer.
 29. The stent of claim 1, wherein the stent sidewall structurefurther comprises a third coating composition comprising a secondtherapeutic agent, wherein the third coating composition is disposed inat least some of the pores.
 30. The stent of claim 29, wherein the firsttherapeutic agent and second therapeutic agent are different.
 31. Thestent of claim 29, wherein the third coating composition furthercomprises a polymer.
 32. The implantable stent of claim 1, wherein thestent sidewall structure comprises the stent strut body and the surfaceis a surface of the stent strut body.
 33. The stent of claim 32, whereinthe surface of the stent strut body is an abluminal surface.
 34. Thestent of claim 32, wherein the pores are distributed throughout thestent strut body.
 35. The stent of claim 32, wherein the pores arehomogenously distributed throughout the stent strut body.
 36. A methodof coating an implantable stent having a stent sidewall structure, thestent sidewall structure comprising a stent strut body having a surfacedefined by the stent strut body or by a surface coating on the stentstrut body, the surface coating comprising a surface coating compositioncomprising a metal, a metal oxide or a ceramic oxide, or inert carbon,the stent sidewall structure defining a plurality of pores therein and,the method comprising: (a) creating a plurality of cavities in thesurface, wherein the cavities have a cavity surface and wherein at leastsome of the pores are in fluid communication with a portion of thecavity surface; (b) disposing a second composition comprising a firsttherapeutic agent within a portion of at least one of the cavities; and(c) forming a cap in the at least one of the cavities to cover thesecond coating composition, wherein the cap is within the at least oneof the cavities and wherein at least some of the pores in the cavitysurface being not covered by the cap and being in fluid communicationwith the surface, thereby causing the first therapeutic agent to releasethrough the pores to the surface and to not substantially release fromthe cavity directly to the surface.
 37. The method of claim 36, whereinthe stent sidewall structure comprises the stent strut body with thesurface coating and the cavities are created in the surface coatingcomposition.
 38. The method of claim 36, further comprising disposingthe second coating composition within at least some of the pores. 39.The method of claim 37, further comprising disposing a third coatingcomposition within at least some of the pores, wherein the third coatingcomposition comprises a second therapeutic agent.
 40. The method ofclaim 36, wherein the cap comprises a polymer.
 41. The method of claim36, wherein the second coating composition further comprises a polymer.42. The method of claim 36, wherein the cavities are created by laserablation, drilling, chemical etching or a combination thereof.
 43. Themethod of claim 36, further comprising disposing a third coatingcomposition within at least some of the pores, wherein the third coatingcomposition comprises a second therapeutic agent.
 44. The method ofclaim 36, wherein the surface of the stent sidewall structure is asurface of the stent strut body, the pores are defined in the stentstrut body, and the cavities are created in the stent strut body.
 45. Amethod of coating an implantable stent having a stent sidewallstructure, the stent sidewall structure comprising a strut and a surfacecoating comprising a surface coating composition comprising a metal, ametal oxide or a ceramic oxide, or inert carbon, the method comprising:(a) creating a plurality of cavities in the metal or ceramic oxide orinert carbon, wherein the cavities have a cavity surface; (b) creating aplurality of pores in the metal or ceramic oxide or inert carbon andwherein at least some of the pores are in fluid communication with aportion of the cavity surface; and (c) disposing a second compositioncomprising a first therapeutic agent within a portion of at least one ofthe cavities; and (d) forming a cap in the at least one of the cavitiesto cover the second coating composition, wherein the cap is within theat least one of the cavities and wherein at least some of the pores inthe cavity surface being not covered by the cap and being in fluidcommunication with the surface, thereby causing the first therapeuticagent to release through the pores to the surface and to notsubstantially release from the cavity directly to the surface.
 46. Themethod of claim 45, further comprising disposing the second compositionwithin at least some of the pores.
 47. The method of claim 45, furthercomprising disposing a third coating composition within at least some ofthe pores, wherein the third coating composition comprises a secondtherapeutic agent.
 48. The method of claim 45, wherein the cap comprisesa polymer.
 49. The method of claim 45, wherein the cavities are formedby laser ablation, drilling, chemical etching or a combination thereof.50. The implantable stent of claim 1, wherein the cap is within the atleast one of the cavities and at least some of the pores in the cavitysurface being not covered by the cap and being in fluid communicationwith the surface.